Short peptides self-assemble to produce catalytic amyloids

Enzymes fold into unique three-dimensional structures, which underlie their remarkable catalytic properties. The requirement to adopt a stable, folded conformation is likely to contribute to their relatively large size (>10,000 Da). However, much shorter peptides can achieve well-defined conformations through the formation of amyloid fibrils. To test whether short amyloid-forming peptides might in fact be capable of enzyme-like catalysis, we designed a series of seven-residue peptides that act as Zn 2+ -dependent esterases. Zn 2+ helps stabilize the fibril formation, while also acting as a cofactor to catalyse acyl ester hydrolysis. These results indicate that prion-like fibrils are able to not only catalyse their own formation, but they can also catalyse chemical reactions. Thus, they might have served as intermediates in the evolution of modern-day enzymes. These results also have implications for the design of self-assembling nanostructured catalysts including ones containing a variety of biological and non-biological metal ions. Amyloid fibril formation is often catalysed by mature fibrils or other aggregates on the fibrillization pathway; however, fibrils cannot normally catalyse other chemical reactions. Here, small seven-residue peptides designed from first principles are shown to form amyloid fibrils that can efficiently catalyse ester hydrolysis.